Abstract The liver is the most regenerative organ in the body following injury or insult, however it is unclear how some components of the liver, namely the extracellular matrix (ECM) and resident macrophages, interact and change with aging. Previous work has identified a significant age-related increase in the number and activation of liver-resident macrophages. Recent studies have also identified the existence of two distinct subsets of macrophages in the liver: Kupffer cells (embryonic origin) and bone marrow derived macrophages. No study to date has examined how these two macrophage subsets are affected by the aging process, which may have major implications for the ability of the host to maintain immune tolerance, as well as respond to infection, injury, and other chronic liver diseases. We hypothesize that the predominant population of liver macrophages will shift from embryonic derived to bone marrow derived macrophages in aged murine livers, with major implications for normal tissue functions. We also hypothesize that changes in the ECM, which composes the macrophage ?niche?, will undergo an increase in stiffness and contribute to macrophage dysfunction with aging. To assess these hypotheses, we have devised two aims: to 1) examine the role of cell ontogeny on the observed increase in resident macrophage number and activation in the aged murine liver and 2) characterize the age-related changes in mechanical and biochemical composition of liver ECM and the effect on the liver-resident macrophages. Our innovative approach involves a transdisciplinary research and mentoring team including basic scientists and engineers using advanced models and techniques such as bone marrow chimeric mice, whole organ decellularization, and biomimetic scaffolds to address our research question. It is critically important to understand how liver macrophage phenotype and function as well as the liver ECM change during aging, and the reciprocal regulation between these two tissue components, to devise new therapies to reduce age-related inflammation and extend healthy aging.